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Original Investigation
January 11, 2022

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial

Author Affiliations
  • 1Institute for Clinical and Translational Research, Cancer and Blood Disorder Institute, and Heart Institute, Johns Hopkins All Children’s Hospital, St Petersburg, Florida
  • 2Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland
  • 3Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
  • 4Department of Biostatistics, School of Public Health, University of Colorado Anschutz Medical Campus, Aurora
  • 5CPC Clinical Research, Aurora, Colorado
  • 6Versiti Blood Research Institute and Department of Pediatrics and Medicine and Clinical and Translational Science Institute, Medical College of Wisconsin, Milwaukee
  • 7Division of Cardiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora
  • 8Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 9Lombardi Cancer Center, Department of Medicine, School of Medicine, Georgetown University, Washington, DC
  • 10Department of Pediatrics, School of Medicine, Children’s Hospital of Colorado, Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora
  • 11Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia
  • 12Department of Medicine, Zucker School of Medicine at Hofstra/Northwell and Feinstein Institutes for Medical Research, Manhasset, New York
  • 13Department of Obstetrics and Gynecology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
  • 14Université de Paris, AP-HP, Hôpital Bichat, French Alliance for Cardiovascular Trials and INSERM 1148, Paris, France
  • 15Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
JAMA. 2022;327(2):129-137. doi:10.1001/jama.2021.23182
Key Points

Question  Among patients younger than 21 years of age with acute provoked venous thromboembolism, is a 6-week duration of anticoagulant therapy noninferior to a conventional 3-month duration?

Findings  In this randomized clinical trial that included 417 patients with provoked venous thromboembolism, anticoagulant therapy for 6 weeks vs 3 months resulted in symptomatic recurrent venous thromboembolism in 0.66% vs 0.70%, respectively, and clinically relevant bleeding events in 0.65% vs 0.70% within 1 year. The differences met the criteria for noninferiority.

Meaning  Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority based on a combination of recurrent venous thromboembolism risk and bleeding risk.

Abstract

Importance  Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown.

Objective  To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age.

Design, Setting, and Participants  Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021.

Interventions  Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism.

Main Outcomes and Measures  The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve).

Results  Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively).

Conclusions and Relevance  Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk.

Trial Registration  ClinicalTrials.gov Identifier: NCT00687882

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